Development of novel HEPT analogs featuring significantly improved anti-resistance potency against HIV-1 through chemical space exploration of the tolerant region I

Our recent great interest in developing 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogs for HIV therapy identified a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) 3 (EC50 = 0.01681 & mu;M), but its therapeutic efficacy was limited by its poor anti-resistance potency. This prompted us to search for po-tential HEPT analogs with broad-spectrum activities, leading to the generation of a series of novel HEPT analogs through exploring the chemical space of the solvent -protein interface. Encouraging improvements in anti-resistance efficacy were observed in some of these analogs, with the most promising compound 7 g being 3 to 26 ¡ fold more potent than 3 against five mutant strains (E138K, Y181C, L100I, K103N, and Y188L). This analog surpassed the activity and selectivity of compound 3 by approximately 2-fold (EC50 = 0.007468 & mu;M, SI = 4260). Furthermore, it was found to demonstrate feeble inhibition of CYP and hERG in vitro, and no in vivo acute toxicity. This study will further enrich the structure-activity relationships (SARs) of the HEPT scaffold, providing new guidance for the development of NNRTIs.

Automated summary

Our recent research on developing HEPT analogs for HIV therapy has identified a potent NNRTI 3 with limited anti-resistance potency. In order to address this limitation, we explored the chemical space of the solvent-protein interface and generated a series of novel HEPT analogs. Some of these analogs showed significant improvements in anti-resistance efficacy, with compound 7g being the most promising, surpassing the activity and selectivity of compound 3 by approximately 2-fold. This study provides new guidance for the development of NNRTIs.